Di-sec-alkyl-dialkylammonium salts and processes for preparing the same



Patented Oct. 19, 1954 UNITED STATES PATENT OFFICE DI-SEC-ALKYL-DIALKYLAMMONIUM SALTS AND PROCESSES FOR PREPARING THE SAM Richard A. Robinson, Morton Grove, Ill., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application May 7, 1951, Serial No. 225,070

6 Claims. (01. 2260-5671)) sents one. equivalent of an anion such as fluoride, chloride, bromide, iodide, sulfate, phosphate, sulfamate, citrate, oxalate, tartrate, ascorbate, succinate, benzenesulfonate and the like, which with the organic cations form salts which are therapeutically acceptable.

The autonomic blocking agent currently used in clinical practice is tetraethylammonium bromide. Its usefulness is rather limited because of the severity of its side reactions and the small margin between the medium effective dose and the toxic range. It is therefore desirable to find compounds which produce ganglion block at a considerably lower dose so as to avoid the undesirable secondary eifects. The compounds which constitute this. invention serve this special purpose.

I have discovered that the presence of. two secondary alkyl radicals. on. the. quaternary nitrogen atom is essential for the production of highly potent automatic blocking agents. If alkyl radicals attached to the nitrogen. atom through primary carbon atoms are used in place of the two alkyl groups attached to nitrogen through secondary carbon atoms, a greatreduction in potency is. observed. This discovery is not suggested or taught'by any of the many publications in this area of medicinal chemistry.

In a paper to be published in the Journal of Pharmacology and Experimental Therapeutics, Martin M. Winbury, Donald L. Cook and Walter E. Hambourger present acomparison of the ganglion blocking effect of three of the compounds described in the examples below and of tetraethylammonium bromide, on an equimolar basis. The results obtained by the technic of Donald L. Cook et al. (Journal of Pharmacology and Experimental Therapeutics, vol. 99, pages 435 et seq.; 1950) are given in the following table. The activity data refer to sympathetic ganglion blockade.

Compound Activity Example Tetraethylammouium bromide 1 Diisopropyldiethylammonium chloride 12. 6 Diisopropylethylmethylammonium bromide 5. 9 2 Di-sec-butylethylmethylammonium iodide 6. 4 3

Comparable activity ratios are observed in the study of parasympathetic ganglion blockade.

In the preparation of certain of the compounds which constitute this invention some difliculties arise, mainly because of steric hindrance. Where the dialkylamino intermediates are not readily available, I employ the reductive alkylation utilizing ammonia, or a primary amine and the appropriate carbonyl compound: (see Emerson, Organic Reactions, vol. IV, page 174: 1948).. Tertiary amines are. obtained by N-methylation by the method of Eschweiler-Clark or N-ethylation by the action of one mol of alkyl halide on two mols of secondary amine. Anomalous results are obtained in certain of the ethylation procedures. Although the reaction proceeds readily at moderate temperatures with either ethyl bromide or ethyl. iodide, the desired alkylation is attained only with the latter reagent. Using ethyl bromide there are indications of. excessive alkene formation and only mixtures are obtained. In the final quaternization step relatively drastic conditions are required- The examples describe the preparation of certain halides. The: halide anion is convertible to other anions; of the. aforementioned type by the usual methods. Thus treatment of a solution of 3' mols of the bromide in absolute isopropanol with one mol of silver citrate and two mols of anhydrous citric acid, stirring at room temperature, removal of the silver bromide by filtration and concentration of the filtrate in vacuo yields the citrate.

My invention will be described more fully in conjunction with the following examples. It should be understood, however, that these e amples' are givenbyway of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details set forth. It will be apparent to those skilled. in the art that manymodifications. in materials and methods may be made without departing from the invention. In each of these examples, temperatures are given in degrees centigrade C.) and quantities of materials as parts by weight.

3 EXAMPLE 1 Diisopropyldiethylammonium chloride To a solution of 202 parts of diisopropylamine in 240 parts of butanone, 156 parts of ethyl iodide are added in small parts in the course of one hour. The temperature is gradually raised to the refluxing range and reflux is maintained for 2.5 7

hours. The precipitated diisopropylamine hydriodide is collected on a filter. The filtrate is then diluted with ether and treated with an excess of a 25% hydrogen chloride solution in isopropanol. The precipitated hydrochloride is collected on a filter and the filtrate evaporated to dryness. The diisopropylethylamine is liberated from the hydrochloride and the final filtrate is distilled at about 126-1265 C.

45 parts of the ethyldiisopropylamine thus obtained are mixed with a solution of 55 parts of ethyl iodide in 100 parts of butanone in a shielded pressure reactor and stored at 70-75 C. for 60 hours. The charge is then heated by steam to 100 C. for 2.5 hours. After cooling the diisopropyldiethylammonium iodide is collected on a filter and washed with hot butanone. The filtrate is subjected to further treatment with ethyl iodide.

122 parts of the iodide, which melts at 227 C., are stirred in aqueous methanol with 6 parts of silver oxide. The mixture is filtered and the filtrate treated with an excess of silver chloride. The silver iodide is filtered off and the methanol removed from the filtrate under vacuum. The resulting chloride is dissolved in isopropanol, filtered through charcoal and precipitated by anhydrous ether. After drying in vacuo and recrystallization from a mixture of isopropanol and ether, the chloride is obtained in the form of colorless crystals which melt at about 223 C. with decomposition.

C2H5 1 CH(CHfl)l EXAMPLE 2 Diz'sopropyZethylmethylammonium bromide A mixture of 140 parts of diisopropylmethylamine, 355 parts of ethyl bromide and 282 parts of nitromethane is heated at reflux temperature for 20 hours. The crystalline precipitate is collected on a filter and washed with ether. An additional crop of crystals is obtained by treatment of the filtrate with ether. Recrystallized from a mixture of isopropanol and ether the diisopropylethylmethylammonium bromide melts at about 249 C. with decomposition. The nitromethane-ether filtrate is freed of its ether by distillation and then submitted to further ethylation by ethyl bromide.

EXAMPLE 3 Di-sec-butylethylmethylammonium iodide A mixture of 270 parts of di-sec-butylmethylamine, 355 parts of ethyl iodide and 565 parts of nitromethane is heated at reflux temperature for 12 hours. The solvent is distilled off in vacuum and the residue washed with ether and then collected on a filter and there washed with butanone until the reddish color disappears. Successive recrystallizations from butanone yield colorless crystals of di-sec-butylethylmethylammonium iodide, melting at about 199 C., which has the structural formula:

CH3 (DH-CH3 I claim: 1. The therapeutically acceptable quaternary ammonium salts of the structural formula N r/zPma-cm RI wherein R, and R. are alkyl radicals of no more than two carbon atoms and X is one equivalent of an anion.

2. The therapeutically acceptable quaternary ammonium salts of the structural formula wherein R is an alkyl radical of no more than two carbon atoms and X is one equivalent of an anion.

3. The therapeutically acceptable diisopropyldiethylammonium salts.

4. The therapeutically acceptable diisopropylethylmethylammonium salts.

5. The therapeutically acceptable quaternary ammonium salts of the structural formula B it GEL-CH;

2115 wherein R, is an alkyl radical of no more than two carbon atoms and X is one equivalent of an anion.

6. The therapeutically acceptable di-sec-butylethylmethylammonium salts.

OTHER REFERENCES Longino et al., Chemical Abstracts, vol. 43 (1949), p. 5496 (Abstract of Proc. Soc. Exptl.) Biol. Med, vol. (1949), pp. 467 to 475.

Caspe, Am. J. Pharm., vol. 114 (1942), pp. 56 to 57. 

1. THE THERAPEUTICALLY ACCEPTABLE QUATERNARY AMMONIUM SALTS OF THE STRUCTURAL FORMULA 